Mechanism of Action: Synera (lidocaine and tetracaine) ™ applied to intact skin provides local dermal analgesia by the release of lidocaine and tetracaine from the patch into the skin. Lidocaine is an amide-type local anes-thetic agent and tetracaine is an ester-type local anesthetic agent. Both lidocaine and tetracaine block sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia.

Pharmacokinetics

Absorption

The amount of lidocaine and tetracaine systemically absorbed from Synera (lidocaine and tetracaine) is thought to be directly related to the duration of application. However, this was not clearly demonstrated in clinical trials. Application of one Synera (lidocaine and tetracaine) patch for 30 minutes in adults produced peak plasma concentrations of lidocaine less than 5 ng/mL while plasma levels of tetracaine were below the limit of quantitation ( < 0.9 ng/mL) in all subjects tested (n = 12, see Table 1). Synera (lidocaine and tetracaine) application up to 60 minutes did not significantly increase plasma levels of lidocaine or tetracaine compared to a 30-minute application.

Table: 1 Absorption of Lidocaine and Tetracaine from Synera (lidocaine and tetracaine) Normal Adult Volunteers (n=12)

Application of Synera (lidocaine and tetracaine) to broken or inflamed skin, or simultaneous or sequential application of multiple Synera (lidocaine and tetracaine) patches could result in higher plasma levels of local anesthetic that could, in susceptible individuals, produce systemic toxicity.

In general, application of multiple Synera (lidocaine and tetracaine) patches either simultaneously or sequentially is not recommended. However, plasma levels of lidocaine and tetracaine have been determined in clinical pharma-cology studies following multiple successive and simultaneous applications of Synera (lidocaine and tetracaine) patches on intact skin.

Maximum plasma levels of lidocaine after the application of a) four successive Synera (lidocaine and tetracaine) patches for 30 minutes each with a 30-minute interval between each patch application, and b) three Synera (lidocaine and tetracaine) patches for 60 minutes each with a 60-minute interval between each application were less than 12 ng/mL and 8 ng/mL, respectively. Tetracaine was not detected in plasma following either treatment.

Simultaneous application of two or four Synera (lidocaine and tetracaine) patches for 60 minutes produced peak plasma concentrations of lidocaine of less than 9 ng/mL, while tetracaine plasma concentrations were not detectable in all subjects (n=22). Sequential 30-minute applications of four Synera (lidocaine and tetracaine) patches at 60-minute intervals produced peak plasma concentrations of lidocaine of less than 12 ng/mL, while tetracaine plasma concentrations were below the limit of quantitation (n=11).

Distribution

When lidocaine is administered intravenously to healthy volunteers, the steady-state volume of distribution is approximately 0.8 to 1.3 L/kg. At lidocaine concentrations observed following the recommended product application, approximately 75% of lidocaine is bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mcg/mL of free base) the plasma protein binding of lidocaine is concentration dependent. Lidocaine crosses the placental and blood brain barriers, presum-ably by passive diffusion. CNS toxicity may typically be observed around 5000 ng/mL of lidocaine; however a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL.

Volume of distribution and protein binding have not been deter-mined for tetracaine due to rapid hydrolysis in plasma.

Metabolism

It is not known if lidocaine or tetracaine is metabolized in the skin. Lidocaine is metabolized rapidly by the liver to a number of metabolites including monoethylglycinexy-lidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that of lidocaine. The major metabolic pathway of lidocaine, sequential N-deethylation to monoethylgly-cinexylidide (MEGX) and glycinexylidide (GX), is primarily mediated by CYP1A2 with a minor role of CYP3A4. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration of lidocaine, MEGX and GX concentrations in serum range from 11% to 36% and from 5% to 11% of lidocaine concen-trations, respectively. Serum concentrations of MEGX were about one-third the serum lidocaine concentrations.

Tetracaine undergoes rapid hydrolysis by plasma esterases. Primary metabolites of tetracaine include para-aminobenzoic acid and diethylaminoethanol, both of which have an unspecified activity.

Elimination

The half-life of lidocaine elimination from the plasma following intravenous administration is approximately 1.8 hr. Lidocaine and its metabolites are excreted by the kidneys. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. Less than 10% of lidocaine is excreted unchanged in adults, and approximately 20% is excreted unchanged in neonates. The systemic clearance is approximately 8-10 mL/min/kg. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours).

The half-life and clearance for tetracaine have not been established for humans, but hydrolysis in the plasma is rapid.

Special Populations

Pediatrics: Application of one Synera (lidocaine and tetracaine) patch for up to 30 minutes in children 4 months to 12 years of age (n=18) produced maximum peak plasma concentrations of lidocaine and tetracaine of 63 ng/mL and 65 ng/mL, respectively. Application of two Synera (lidocaine and tetracaine) patches for up to 30 minutes to children 4 months to 12 years of age (n=19) produced peak lidocaine levels of up to 331 ng/mL and tetracaine levels of less than 5 ng/mL.

Elderly: After application of one Synera patch for 20 minutes, plas-ma levels of lidocaine and tetracaine were not detectable in elderly subjects ( > 65 years of age, mean 72.0 ±4.3 years, n=10). After simultaneous application of two Synera (lidocaine and tetracaine) patches for 60 minutes to elderly subjects ( > 65 years of age, mean 69.5 ±3.7 years, n=12), the maximum peak lidocaine concentration was 6 ng/mL and tetracaine was not detectable. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours).

Cardiac, Renal and Hepatic Impairment: No specific pharmacokinetic studies were conducted. The half-life of lidocaine may be increased in cardiac or hepatic dysfunction. There is no established half-life for tetracaine due to rapid hydrolysis in the plasma.

Clinical Studies

Superficial Venous Access

Three randomized, double-blind, placebo controlled clinical trials in adult and geriatric subjects evaluated the degree of dermal analgesia upon venipuncture following a 20-minute treatment with Synera (lidocaine and tetracaine) or a placebo patch (patch with heating component but no drug). In each trial, subjects received Synera (lidocaine and tetracaine) on one arm and placebo patch on the other. Less pain was reported following Synera (lidocaine and tetracaine) treatment compared to placebo in all three studies as measured by a 100 mm visual analog scale (VAS). In the first study in 21 subjects, median VAS scores for Synera (lidocaine and tetracaine) and placebo treatments were 1 and 9, respectively. In the second study in 40 subjects, median VAS scores were 5 and 28 for Synera (lidocaine and tetracaine) and placebo treatments, respectively. In the third study, in 40 subjects over the age of 65 years, median VAS scores for Synera (lidocaine and tetracaine) and placebo treatments were 8 and 14, respectively.

In a randomized, double-blind, placebo controlled study, 61 pediatric patients received either Synera (lidocaine and tetracaine) or placebo for 20 minutes prior to venipuncture or IV cannulation in the antecubital fossa or dorsum of the hand. Subjects were stratified by age group (3 to 6 years and 7 to 17 years). Children in the younger group reported less pain with Synera (lidocaine and tetracaine) than with placebo, as rated using a six-point Oucher pain scale with faces. Children in the older group rated their pain using a different instrument; an eleven-point Oucher pain scale that contained both faces and numbers. Pain scores in the older children treated with Synera (lidocaine and tetracaine) were not statistically significantly different from pain scores in those treated with placebo.

In a double-blind trial in 250 adults, subjects were randomized to receive either Synera (lidocaine and tetracaine) without heating element or intact, heated Synera (lidocaine and tetracaine) , prior to venipuncture. Less pain was reported following treatment with the heated Synera (lidocaine and tetracaine) compared to the non-heated patch. Median VAS scores for the patch with the heating component and without the heating component were 17 and 22, respectively.

Superficial Dermatological Procedures

In one randomized, double-blind, placebo controlled study, 94 adult subjects received either Synera (lidocaine and tetracaine) or placebo patch for 30 minutes prior to a superficial dermatological procedure such as superficial excision, shave biopsy or electrodessication. Less pain was reported following Synera (lidocaine and tetracaine) treatment compared to placebo. Median VAS scores for Synera (lidocaine and tetracaine) and placebo treatments were 5 and 31, respectively. In a similarly designed study in 74 subjects over the age of 65 years, less pain was reported following Synera (lidocaine and tetracaine) treatment compared to placebo with median VAS scores for Synera (lidocaine and tetracaine) and placebo treatments of 10 and 23, respectively.

In a randomized, double-blind, placebo controlled study, 88 pediatric patients were stratified by age group (3 to 6 years and 7 to 17 years) to receive a 30-minute application of either Synera (lidocaine and tetracaine) or placebo, prior to lidocaine injection. In younger children who used the Oucher pain scale with faces, those receiving Synera (lidocaine and tetracaine) reported less pain from lidocaine injection than those receiving placebo. Older children used the numerical Oucher pain scale to report pain intensity. There was no difference between treatments observed in the older children.

Last reviewed on RxList: 1/23/2009
This monograph has been modified to include the generic and brand name in many instances.